This application proposes the formation of a University of Michigan (UM) EDRN Biomarker Development Lab (BDL). Through previous EDRN BDLs, our team has characterized multiple important prostate cancer biomarkers, most notably TMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. Sanda PI), we have developed, validated and clinically implemented Mi-Prostate Score (MiPS), a prostate cancer early detection test incorporating urine quantification of two prostate cancer specific transcripts—the TMPRSS2:ERG gene fusion and PCA3—with serum PSA. Introduced in our CLIA laboratory (and now with New York State approval), MiPS helps shared decision making after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Here, using this work as a model, we will discover and characterize aggressive prostate cancer transcriptomic biomarkers, focusing on long non-coding RNAs (lncRNAs). Although lncRNA biomarker utility has been largely unexplored, we recently characterized the lncRNA compendium (“MiTranscriptome”), identifying several prostate cancer-specific and aggressive prostate cancer-specific lncRNAs. Supporting our proposed approach, we have performed initial validation of the lncRNA SChLAP1 as an aggressive prostate cancer specific biomarker in tissues. Likewise, we have developed RT-PCR based next generation sequencing (NGS) panels capable of quantifying multiplexed transcriptomic biomarkers in archived tissue and urine. Here, in three Aims, we will nominate and develop transcriptomic biomarkers as predictors of aggressive prostate cancer both at and prior to diagnosis. In Aim 1, we will identify novel aggressive prostate cancer-associated transcriptomic alterations from our MiTranscriptome analysis. We will develop single gene and multiplexed NGS assays to study these lncRNAs/coding transcripts as aggressive prostate cancers specific biomarkers. In Aim 2 we will characterize transcripts from Aim 1 as tissue based aggressive prostate cancer biomarkers. Following our previous approach with SChLAP1, we will develop individual in situ hybridization assays and a multiplexed NGS panel to characterize these transcripts in well characterized prostate cancer tissue cohorts. In Aim 3, we will characterize transcripts identified in Aim 1 as non-invasive, urine-based aggressive prostate cancer early detection biomarkers. Through collaboration with Hologic/Gen-Probe (our industry partner on MiPS), we will develop and assesses the performance of individual prioritized biomarkers using their platform on our biobanked urine samples. Additionally, using multiplexed NGS, we will also characterize the performance of a panel of transcriptomic biomarkers as an alternative/complementary approach. As recognized by the EDRN, novel aggressive prostate cancer specific biomarkers are urgently needed. Importantly, our approach extends beyond prostate cancer and our BDL, and our group has actively participated in the EDRN biomarker community and anticipates continuing work with other BDLs and CVCs to facilitate the overall EDRN mission.